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WO2025217430A1 - Composés hétérocycliques utilisés en tant qu'inhibiteurs de nras - Google Patents

Composés hétérocycliques utilisés en tant qu'inhibiteurs de nras

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Publication number
WO2025217430A1
WO2025217430A1 PCT/US2025/024118 US2025024118W WO2025217430A1 WO 2025217430 A1 WO2025217430 A1 WO 2025217430A1 US 2025024118 W US2025024118 W US 2025024118W WO 2025217430 A1 WO2025217430 A1 WO 2025217430A1
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WIPO (PCT)
Prior art keywords
fluoro
alkyl
compound
chosen
tert
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PCT/US2025/024118
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English (en)
Inventor
Joshua Cox
Naphtali REYNA
Tuyen Ngoc Phuong TRAN
Vinay Nair
Edith NAGY
Michael J. Soth
Pijus K. Mandal
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University of Texas System
University of Texas at Austin
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University of Texas System
University of Texas at Austin
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Publication of WO2025217430A1 publication Critical patent/WO2025217430A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • RAS proteins serve a critical role in cell proliferation as they regulate signal transduction received from extracellular stimuli to downstream pathways such as MAPK, PI3K-AKT and Ral-GDS. These pathways are involved in cellular events such as cell cycle, cell differentiation and cell survival. Dysregulation in RAS signaling is most often associated with activating mutations in the RAS protein typically found at codons 12,13 and 61. Such activating mutations break down the cycling between active (GTP-bound) and inactive (GDP-bound) RAS leading to cancer.
  • NRAS mutant-driven acute myeloid leukemia accounts for 11-30% of all AML patients. 44% of occurring mutation in AML is observed at codon 12 (NRAS G12D represents 30%) followed by codon 13 and 61. In contrast, in melanoma, NRAS mutations are predominantly observed at codon 61 and to a lesser extent at codons 12 and 13.
  • Targeting RAS mutant cancers has been historically challenging. After the initial failed attempts to prevent KRAS attachment and activation in the membrane by using famesyl transferase inhibitors, focus has shifted to upstream and downstream targets in the RAS signaling pathway. Inhibition of RTKs (receptor tyrosine kinases), SHP2 and SOS, all found upstream of RAS, has shown limited impact on RAS driven cancers, while regulation of downstream proteins such as MEK, RAF and PI3K are often plagued by toxicity issues. However, it has been discovered that directly targeting the mutant RAS proteins offers new possibilities for inhibiting the main oncogene.
  • KRAS G12C mutant tumors have been demonstrated in the clinic to be an effective mode of treatment of NSCLC (non-small cell lung cancer), resulting in the FDA approval of sotorasib. Others have shown that KRAS G12D mutant cancers can also be targeted with non-covalent inhibitors, with the non-conserved KRAS residue H95 theorized to play a significant role in binding selectivity. [005] Despite the significant attention focused on targeting RAS mutants, there exists a need for compounds and methods for the treatment of RAS G12D-mediated diseases, specifically NRAS G12D-mediated diseases. The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.
  • Embodiment 1 Provided in Embodiment 1 is a compound of Formula I, or a salt or tautomer thereof, wherein
  • J 1 , J 2 and J 3 are independently chosen from CR 12 and N;
  • J 4 is chosen from N, NR 12 , CH and S;
  • X is chosen from CR 5 and NR 5 ;
  • Y is chosen from CR 6 , N, and NR 6 ;
  • Z is chosen from CR 7 , N, and NR 7 ;
  • R 1 is chosen from H, alkyl, halo, OH, and NH2;
  • R 2 is chosen from H, alkyl, and halo
  • R 3 is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SF5;
  • R 4 is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R 8 ; or R 4 and R 12 , taken together, form a 5- membered heteroaryl;
  • R 5 is chosen from either of which may be optionally substituted by one or more R 9 ;
  • R 6 is chosen from H, amino, alkyl, alkynyl, heteroaryl, and cyano, wherein alkyl and alkynyl may be optionally substituted by one or more groups chosen from hydroxy, cyano, -N(R 13 ) 2 , -NHC(O)-R 14 , -C(O)N(R 15 ) 2 , -NHS(O) 2 -alkyl, heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino, wherein heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino are optionally substituted with halo or alkyl, or R 6 and R 7 , taken together, form a 6-membered heterocycloalkyl optionally substituted with one or more R 16 ; or R 6 and R 9 , taken together, form - CH 2 O(CH 2 ) 4 O
  • R 7 is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may be optionally substituted by one or more R 10 ; each R 8 is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, - C(O)NH 2 , and oxo; each R 9 is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R 13
  • R 14 is chosen from alkyl, cyanoalkyl, hydroxyalkyl, alkoxy, and heteroaryl; each R 15 is independently chosen from H and alkyl; and each R 16 is independently chosen from halo and alkyl.
  • a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • Also provided are methods of inhibiting at least one NR AS GI2D function comprising the step of contacting NRAS G12D with a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the cell phenotype, cell proliferation, activity of NRAS G12D, change in biochemical output produced by active NRAS G12D, expression of NRAS G12D, or binding of NRAS G12D with a natural binding partner may be monitored.
  • Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.
  • NRAS G12D-mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • a method of inhibition of NRAS G12D comprising contacting NRAS G12D with a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.
  • Also provided is a method of modulation of an NRAS G12D-mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms.
  • alkoxy and, interchangeably, “(alkyl)oxy”, as used herein, refers to an alkyl radical attached to a molecule by oxygen.
  • alkyl refers to a straight-chain or branched-chain saturated, hydrocarbon radical containing from 1 to 20 carbon atoms. In some embodiments, alkyl will comprise from 1 to 10 carbon atoms. In some embodiments, alkyl will comprise from 1 to 8 carbon atoms.
  • alkylamino refers to an alkyl group attached to the parent molecular moiety through an amino group.
  • dialkylamino refers to two alkyl groups attached to the parent molecular moiety through an amino group.
  • amido and “carbamoyl,” as used herein, refer to an amino or alkylamino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa.
  • amino refers to -NH2.
  • aryl as used herein, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.
  • cyano refers to -CN.
  • cycloalky refers to a saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. In some embodiments, cycloalkyl will comprise from 5 to 7 carbon atoms. In some embodiments, cycloalkyl will comprise a spirocyclic ring system. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, as well as the multicyclic (multicentered) saturated type.
  • halo refers to fluorine, chlorine, bromine, or iodine.
  • haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • heteroaryl refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from N, O, and S.
  • heteroaryl will comprise from 1 to 4 heteroatoms as ring members.
  • heteroaryl will comprise from 1 to 2 heteroatoms as ring members.
  • heteroaryl will comprise from 5 to 7 atoms.
  • heterocyclic rings are fused with aryl rings wherein heteroaryl rings are fused with other heteroaryl rings wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.
  • heterocycloalkyl and, interchangeably, “heterocycle,” as used herein, refers to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bridged; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bicyclic; or saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) tricyclic heterocyclic group containing at least one heteroatom as a ring member wherein each heteroatom may be independently chosen from nitrogen, oxygen, and sulfur.
  • heterocycloalkyl will comprise a spirocyclic ring system. In some embodiments, heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In some embodiments, heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In some embodiments, heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In some embodiments, heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In some embodiments, heterocycloalkyl will comprise from 5 to 6 ring members in each ring.
  • Heterocycloalkyl and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl or heteroaryl group, as defined herein, or an additional heterocycle group.
  • hydroxy and, interchangeably, “hydroxyl,” as used herein, refers to - OH.
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • Asymmetric centers exist in the compounds and pharmaceutically acceptable salts thereof, disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof.
  • stereoisomers of compounds, and pharmaceutically acceptable salts thereof can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds, and pharmaceutically acceptable salts thereof, of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds, and pharmaceutically acceptable salts thereof, disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti,
  • administering to a patient refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.
  • therapeutically effective is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.
  • the precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art.
  • the effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.
  • patient is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
  • Embodiment 2 The compound of embodiment 1, or a salt or tautomer thereof, wherein
  • Embodiment 3 The compound of embodiment 2, or a salt or tautomer thereof, wherein J 2 is N and J 3 is CH.
  • Embodiment 4 The compound of embodiment 2, or a salt or tautomer thereof, wherein J 2 is CH and J 3 is N.
  • Embodiment 5 The compound of embodiment 2, or a salt or tautomer thereof, wherein J 2 is CF and J 3 is N.
  • Embodiment 6 The compound of embodiment 2, or a salt or tautomer thereof, wherein J 2 and J 3 are CH.
  • Embodiment 8 The compound of embodiment 2, or a salt or tautomer thereof, wherein R 1 is OH.
  • Embodiment 9 The compound of embodiment 2, or a salt or tautomer thereof, wherein R 2 is chosen from H, methyl, fluoro, and chloro.
  • Embodiment 10 The compound of embodiment 2, or a salt or tautomer thereof, wherein R 3 is chosen from trifluoromethyl, trifluoromethoxy, chloro, and -SFs.
  • Embodiment 13 The compound of embodiment 11 , or a salt or tautomer
  • Embodiment 15 The compound of embodiment 14, or a salt or tautomer thereof, wherein J 2 is CR 12 , wherein R 12 is -NH2.
  • Embodiment 16 The compound of embodiment 14, or a salt or tautomer thereof, wherein J 2 is N.
  • Embodiment 17 The compound of embodiment 14, or a salt or tautomer thereof, wherein J 3 is CR 12 , wherein R 12 is cyano.
  • Embodiment 18 The compound of embodiment 14, or a salt or tautomer thereof, wherein J 3 is N.
  • Embodiment 19 The compound of embodiment 14, or a salt or tautomer thereof, wherein J 4 is CH.
  • Embodiment 20 The compound of embodiment 14, or a salt or tautomer thereof, wherein J 4 is S.
  • Embodiment 21 The compound of embodiment 14, or a salt or tautomer thereof, wherein J 4 is N.
  • Embodiment 22 The compound of embodiment 14, or a salt or tautomer thereof, wherein R 2 is chosen from H and fluoro.
  • Embodiment 23 The compound of embodiment 14, or a salt or tautomer thereof, wherein R 1 is chosen from H and methyl.
  • Embodiment 24 The compound of embodiment 14, or a salt or tautomer thereof, wherein R 3 is chosen from H and chloro.
  • Embodiment 25 The compound of embodiment 14, or a salt or tautomer thereof, wherein Q is chosen from
  • Embodiment 26 The compound of embodiment 25, or a salt or tautomer thereof, wherein
  • Embodiment 27 The compound of any one of embodiments 1 to 26, or a salt or tautomer thereof, wherein R 4 is chosen from H, ethyl, isopropyl, isobutyl, isopropoxy, cyclopropyl, 1 -methylcyclopropyl, tetrahydrofuran-2-ol, propylnitrile, propan- l-ol, trifluoroprop- l-en-2-yl, phenyl, propenyl, cyclopentenyl, 1-methylpyrazolyl, dimethylamino, isobutanol, aminoethanol, isobutanone, acetonitrile, isobutylnitrile, methoxyisopropyl,
  • Embodiment 28 The compound of any one of embodiments 1 to 26, or a salt or tautomer thereof, wherein R 4 is chosen from alkyl, cycloalkyl, and cyanoalkyl.
  • Embodiment 29 The compound of embodiment 28, wherein R 4 is chosen from isopropyl, cyclopropyl, and propylnitrile.
  • Embodiment 30 The compound of embodiment 29, wherein R 4 is isopropyl.
  • Embodiment 31 The compound of embodiment 29, wherein R 4 is cyclopropyl.
  • Embodiment 32 The compound of embodiment 29, wherein R 4 is propylnitrile.
  • Embodiment 33 The compound of any one of embodiments 1 to 32, or a salt or tautomer thereof, wherein J 1 is N.
  • Embodiment 34 The compound of any one of embodiments 1 to 33, or a salt or tautomer thereof, wherein X is CR 5 .
  • Embodiment 35 The compound of embodiment 34, or a salt or tautomer
  • Embodiment 36 The compound of embodiment 35, or a salt or tautomer thereof, wherein R 5 is chosen from
  • Embodiment 37 The compound of embodiment 36, or a salt or tautomer thereof, wherein
  • Embodiment 38 The compound of embodiment 36, or a salt or tautomer thereof, wherein
  • Embodiment 39 The compound of embodiment 36, or a salt or tautomer thereof, wherein [087] Embodiment 40 - The compound of any one of embodiments 1 to 39, or a salt or tautomer thereof, wherein Y is CR 6 .
  • Embodiment 41 The compound of embodiment 40, or a salt or tautomer thereof, wherein R 6 is chosen from hydroxyalkynyl and -alkyl-NHC(O)-R 14 .
  • Embodiment 42 The compound of embodiment 41 , or a salt or tautomer thereof, wherein R 6 is hydroxyalkynyl.
  • Embodiment 43 The compound of embodiment 42, or a salt or tautomer thereof, wherein
  • Embodiment 44 The compound of embodiment 41 , or a salt or tautomer thereof, wherein R 6 is chosen from hydroxyalkynyl and -alkyl-NHC(O)-R 14 .
  • Embodiment 45 The compound of embodiment 44, or a salt or tautomer thereof, wherein
  • Embodiment 46 The compound of any one of embodiments 1 to 39, or a salt or tautomer thereof, wherein Y is N.
  • Embodiment 47 The compound of any one of embodiments 1 to 46, or a salt or tautomer thereof, wherein Z is NR 7 .
  • Embodiment 48 The compound of embodiment 47, or a salt or tautomer thereof, wherein R 7 is cyclopropyl optionally substituted with R 10 .
  • Embodiment 49 The compound of embodiment 48, or a salt or tautomer thereof, wherein R 7 is cyclopropyl.
  • Embodiment 50 The compound of embodiment 48, or a salt or tautomer thereof, wherein
  • Embodiment 51 The compound of any one of embodiments 1 to 50, or a salt or tautomer thereof, wherein
  • X is CR 5 ;
  • Y is CR 6 ;
  • Z is NR 7 .
  • Embodiment 52 The compound of any one of embodiments 1 to 50, or a salt or tautomer thereof, wherein J 1 is N;
  • X is CR 5 ;
  • Y is N; and Z is NR 7 .
  • Embodiment 53 The compound of embodiment 1 , or a salt or tautomer thereof, having a structural formula of Formula II: wherein n is 0, 1 , or 2
  • J 2 and J 3 are independently chosen from CR 12 and N;
  • Y is chosen from CR 6 , N, and NR 6 ;
  • R 1 is chosen from H, alkyl, halo, OH, and NH2;
  • R 2 is chosen from H, alkyl, and halo
  • R 3 is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SB;
  • R 4 is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R 8 ; or R 4 and R 12 , taken together, form a 5 -membered heteroaryl;
  • R 6 is chosen from H, amino, alkyl, alkynyl, heteroaryl, and cyano, wherein alkyl and alkynyl may be optionally substituted by one or more groups chosen from hydroxy, cyano, -N(R 13 )2, -NHC(O)-R 14 , -C(O)N(R 1S )2, alkyl-S(O)2NH-, heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino, wherein heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino are optionally substituted with halo or alkyl; or R 6 and R 9 , taken together, form -CH2O(CH2)4OCH2O-;
  • R 7 is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may be optionally substituted by one or more R 10 ; each R 8 is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, -C(0)NH2, and oxo; each R 9 is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R 13 )2, and
  • R 14 is chosen from alkyl, cyanoalkyl, hydroxyalkyl, alkoxy, and heteroaryl; each R 15 is independently chosen from H and alkyl; and each R 16 is independently chosen from halo and alkyl.
  • Embodiment 54 The compound of embodiment 1, or a salt or tautomer thereof, having a structural formula of Formula III: wherein n is 0, 1 , or 2
  • J 2 and J 3 are independently chosen from CR 12 and N;
  • Y is chosen from CR 6 , N, and NR 6 ;
  • R 1 is chosen from H, alkyl, halo, OH, and NH2;
  • R 2 is chosen from H, alkyl, and halo
  • R 3 is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SFs;
  • R 4 is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R 8 ; or R 4 and R 12 , taken together, form a 5 -membered heteroaryl;
  • R 6 is chosen from H, amino, alkyl, alkynyl, heteroaryl, and cyano, wherein alkyl and alkynyl may be optionally substituted by one or more groups chosen from hydroxy, cyano, -N(R 13 )2, -NHC(O)-R 14 , -C(O)N(R 15 )2, alkyl-S(O)2NH-, heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino, wherein heteroaryl, heterocycloalkyloxy, and heterocycloalkylamino are optionally substituted with halo or alkyl; or R 6 and R 9 , taken together, form -CH2O(CH2)4OCH2O-;
  • R 7 is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may he optionally substituted by one or more R 10 ; each R 8 is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, -C(0)NH2, and oxo; each R 9 is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R 13 )2,
  • R 14 is chosen from alkyl, cyanoalkyl, hydroxyalkyl, alkoxy, and heteroaryl; each R 15 is independently chosen from H and alkyl; and each R 16 is independently chosen from halo and alkyl.
  • Embodiment 55 The compound of embodiment 1, or a salt or tautomer thereof, having a structural formula of Formula IV : wherein:
  • A is a 6-membered heterocycloalkyl; m is 0, 1, 2, 3, 4; n is 0, 1, or 2;
  • J 2 and J 3 are independently chosen from CR 12 and N;
  • Y is chosen from CR 6 , N, and NR 6 ;
  • R 1 is chosen from H, alkyl, halo, OH, and NH2;
  • R 2 is chosen from H, alkyl, and halo
  • R 3 is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, halo, and -SB;
  • R 4 is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R 8 ; or R 4 and R 12 , taken together, form a 5 -membered heteroaryl; each R 8 is independently chosen from halo, alkyl, alkoxy, cyano, hydroxy, haloalkyl, -C(O)NH2, and oxo; each R 9 is independently chosen from alkyl, amido, -C(O)O-alkyl, -C(O)O- cycloalkyl, -C(O)N(R 13 )2, and heteroaryl, wherein
  • Embodiment 56 The compound of embodiment 55, or a salt or tautomer thereof, wherein
  • Embodiment 57 The compound of embodiment 1, or a salt or tautomer thereof, wherein the compound of Formula I has a structural formula chosen from:
  • Embodiment 58 The compound of embodiment 57, or a salt or tautomer thereof, wherein the compound of Formula I has a structural formula chosen from:
  • Embodiment 59 - A pharmaceutical formulation comprising a compound as recited in any one of embodiments 1-58, or a salt or tautomer thereof, together with a pharmaceutically acceptable carrier.
  • Embodiment 60 The pharmaceutical formulation as recited in embodiment 59, formulated for oral administration.
  • Embodiment 61 The pharmaceutical formulation as recited in embodiment 59 or 60, additionally comprising another therapeutic agent.
  • Embodiment 62 - A method of inhibition of NRAS G12D, comprising contacting NRAS G12D with a compound as recited in any one of embodiments 1-58, or a salt or tautomer thereof, or a pharmaceutical composition as recited in any one of embodiments 59- 61.
  • Embodiment 63 - A method of treatment of an NRAS G12D-mediated disease, comprising the administration of a therapeutically effective amount of a compound as recited in any one of embodiments 1-58, or a salt or tautomer thereof, or a pharmaceutical composition as recited in any one of embodiments 59-61, to a patient in need thereof.
  • Embodiment 64 The method as recited in embodiment 63, wherein the NRAS G12D-mediated disease is cancer.
  • Embodiment 65 The method as recited in embodiment 64, wherein the cancer is chosen from Melanoma, Malignant Solid Tumors, Colorectal Carcinoma, Non-Small Cell Lung Carcinoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Colorectal Adenocarcinoma, Multiple Myeloma, Non-Hodgkin Lymphoma, Pancreatic Carcinoma, Cutaneous Melanoma, Ovarian Carcinoma, Pancreatic Ductal Adenocarcinoma, Acute Lymphoblastic Leukemia, Thyroid Gland Carcinoma, Glioma, Neurofibromatosis, Poorly Differentiated Thyroid Gland Carcinoma, Myelodysplastic Syndrome With Excess Blasts, Juvenile Myelomonocytic Leukemia, Histiocytic And Dendritic
  • J 1 , J 2 and J 3 are independently chosen from CR 12 and N;
  • J 4 is chosen from N, CH and S;
  • X is chosen from CR 5 and NR 5 ;
  • Y is chosen from CR 6 , N, and NR 6 ;
  • Z is chosen from CR 7 , N, and NR 7 ;
  • R 1 is chosen from H, alkyl, halo, OH and NH2;
  • R 2 is chosen from H, alkyl, and halo
  • R 3 is chosen from H, alkyl, alkoxy, haloalkyl, haloalkoxy, and halo;
  • R 4 is chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, amino, alkylamino, and dialkylamino may be optionally substituted by one or more R s ;
  • R 5 is chosen from either of which may be optionally substituted by one or more R 9 ;
  • R 6 is chosen from H, alkyl, and cyano, wherein alkyl may be optionally substituted by one or more groups chosen from hydroxy, amino, alkylamino, and dialkylamino;
  • R 7 is chosen from H, alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl, wherein alkyl, amino, alkylamino, dialkylamino, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, haloalkyl, sulfoxyalkyl, aryl, and heteroaryl may be optionally substituted by one or more
  • R 11 is chosen from alkoxy, hydroxy, amino, alkylamino, dialkylamino, and halo; and each R 12 is independently chosen from H, alkyl, amino, and cyano.
  • Embodiment 67 In some embodiments,
  • Embodiment 68 In some embodiments,
  • J 2 is CH.
  • J 3 is CH.
  • Embodiment 72 In some embodiments, R 1 is NH 2 .
  • Embodiment 73 - In some embodiments, R 1 is OH.
  • R 2 is chosen from H, methyl, fluoro, and chloro.
  • R 3 is chosen from trifluoromethyl, trifluoromethoxy, and chloro.
  • Embodiment 76 In some embodiments,
  • R 1 is NH 2 ;
  • R 2 is methyl
  • R is trifluoromethyl.
  • Q is chosen from
  • Embodiment 79 In some embodiments,
  • J 2 is CR 12 , wherein R 12 is -NH2.
  • J 3 is CR 12 , wherein R 12 is cyano.
  • Embodiment 84 In some embodiments, J 4 is CH.
  • Embodiment 85 In some embodiments, J 4 is S.
  • R 2 is chosen from H and fluoro.
  • R 1 is chosen from H and methyl
  • R 3 is chosen from H and chloro.
  • R 4 is chosen from H, ethyl, isopropyl, isobutyl, isopropoxy, cyclopropyl, tetrahydrofuran-2-ol, propylnitrile, propan- l-ol, trifluoroprop- l-en-2-yl, phenyl, propenyl, cyclopentenyl, 1-methylpyrazolyl, dimethylamino, isobutanol, aminoethanol, isobutanone, isobutylnitrile, methoxyisopropyl, and pentyldinitrile.
  • R 4 is chosen from propylnitrile and isopropyl.
  • J 1 is CH.
  • Embodiment 95 In some embodiments, J 1 is N.
  • Embodiment 96 - In some embodiments, X is CR 5 .
  • Embodiment 98 In some embodiments,
  • Embodiment 99 is CR 6 .
  • Embodiment 100 is H.
  • Embodiment 101 - In some embodiments, Y is N.
  • R 7 is chosen from methyl, cyclopropyl, cyclopropylcarboxamide, and cyclopropylnitrile.
  • Embodiment 104 In some embodiments, R 7 is cyclopropyl.
  • Embodiment 105 In some embodiments,
  • X is CR 5 ;
  • Y is N
  • Z is NR 7 .
  • Embodiment 106 the compound has a structural formula of Formula II: or a salt or tautomer thereof, wherein n is 0, 1, or 2 and wherein Y, J 2 , J 3 , R 1 , R 2 , R 3 , R 4 , R 7 , and R 9 are as defined herein.
  • Embodiment 107 The compound of embodiment 1 , or a salt or tautomer thereof, having a structural formula of Formula III: or a salt or tautomer thereof, wherein n is 0, 1, or 2 and wherein Y, J 2 , J 3 , R 1 , R 2 , R 3 , R 4 , R 7 , and R 9 are as defined herein.
  • the compounds disclosed herein can exist as pharmaceutically acceptable salts.
  • the present disclosure includes compounds listed herein in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable.
  • Pharmaceutical Salts Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).
  • salts or zwitterionic forms of the compounds disclosed herein represent salts or zwitterionic forms of the compounds disclosed herein.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenyl
  • acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
  • the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, Mdimelhylaniline, Mmethylpiperidine, Wmethylmorpholine, dicyclohexylamine, procaine, dibenzylamine, JV.JV-dibenzylphenethylamine, 1 -ephenamine, and A r -dibenzylethylenediamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound, or pharmaceutically acceptable salts thereof, of the subject disclosure or a pharmaceutically acceptable salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient.
  • Compounds, or pharmaceutically acceptable salts thereof may be administered at a dose of from 0.1 to 500 mg / kg per day.
  • the dose range for adult humans is generally from 5 mg to 2 g / day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds, or pharmaceutically acceptable salts thereof can be administered in various modes.
  • the pharmaceutical formulation is formulated for oral administration.
  • the compounds described herein may be administered in combination with another therapeutic agent.
  • another therapeutic agent such as one of the side effects experienced by a patient upon receiving one of the compounds herein, or pharmaceutically acceptable salt thereof, is hypertension.
  • the therapeutic effectiveness of one of the compounds described herein, or pharmaceutically acceptable salts thereof may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit of experienced by a patient may be increased by administering one of the compounds described herein, or pharmaceutically acceptable salts thereof, with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
  • Also provided are methods of inhibiting at least one NRAS G12D function comprising the step of contacting NRAS G12D with a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the cell phenotype, cell proliferation, activity of NRAS G12D, change in biochemical output produced by active NRAS G12D, expression of NRAS G12D, or binding of NRAS G12D with a natural binding partner may be monitored.
  • Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.
  • Also provided are methods of treatment of an NRAS G12D-mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • a method of inhibition of NRAS G12D comprising contacting NRAS G12D with a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.
  • Also provided is a method of modulation of an NRAS G12D-mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the NRAS G12D-mediated disease is cancer.
  • the cancer is chosen from Melanoma, Malignant Solid
  • Tumors Colorectal Carcinoma, Non-Small Cell Lung Carcinoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Colorectal Adenocarcinoma, Multiple Myeloma, Non-Hodgkin Lymphoma, Pancreatic Carcinoma, Cutaneous Melanoma, Ovarian Carcinoma, Pancreatic Ductal Adenocarcinoma, Acute Lymphoblastic Leukemia, Thyroid Gland Carcinoma, Glioma, Neurofibromatosis, Poorly Differentiated Thyroid Gland Carcinoma, Myelodysplastic Syndrome With Excess Blasts, Juvenile Myelomonocytic Leukemia, Histiocytic And Dendritic Cell Neoplasm, Head And Neck Squamous Cell Carcinoma, Small Cell Lung Carcinoma, Low Grade Glioma, S
  • Step 1 to a suspension of a compound of Formula 101 in a polar solvent, such as dioxane, is added a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium(0), a ligand, such as tricyclohexylphosphine, a Lewis acid, such as lithium chloride, and tributyl(tributylstannyl)stannane.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • a ligand such as tricyclohexylphosphine
  • a Lewis acid such as lithium chloride
  • tributyl(tributylstannyl)stannane tributyl(tributylstannyl)stannane.
  • the mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred for 24-48 h.
  • the product, a compound of Formula 102 is isolated
  • the mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred for 16-24 h.
  • the product may be subsequently subjected to any set of deprotection conditions known in the art.
  • the product, a compound of Formula I is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.
  • the mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred for 16-48 h.
  • the product, a compound of Formula 202 is isolated and purified using methods known in the art.
  • the mixture is stirred, optionally at elevated temperatures. In some embodiments, the mixture is stirred for 16-24 h.
  • the product may be subsequently subjected to any set of deprotection conditions known in the art.
  • the product, a compound of Formula I is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.
  • a compound of Formula 301 in a polar solvent such as tetrahydrofuran
  • a metalating agent such as lithium chloro-(2,2,6,6-tetramethyl-l-piperidyl)magnesium chloride
  • a brominating agent such as l ,2-dibromo- l ,l ,2,2-tetrachloro-ethane
  • a catalyst such as 1 , 1 ’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
  • a base such as cesium carbonate
  • a catalyst such as a combination of [4,4'-bis( 1 , 1 - dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride, 4,4'-£>A(l,l-dimethylethyl)-2,2’- bipyridine-Al,Ain A[3,5-difhioro-2-[5-(trifluoromethyl)-2-pyridinyl-A]phenyl- C]iridium(III) hexafluorophosphate, tris (trimethylsilyl)silane, and a base, such as sodium carbonate, in the presence of 455 nm blue LED light, to give a compound of Formula 305.
  • a catalyst such as a combination of [4,4'-bis( 1 , 1 - dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride, 4,4'-£>A(l,l-dimethylethyl)
  • the compound of Formula 305 in a polar solvent such as tetrahydrofuran is reacted with a compound of Formula 306 in the presence of a catalyst, such as [(di(l-adamantyl)- butylphosphine)-2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3), and a base, such as tripotassium phosphate, to give a compound of Formula 307.
  • a catalyst such as [(di(l-adamantyl)- butylphosphine)-2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3)
  • a base such as tripotassium phosphate
  • the product may be subsequently subjected to any set of deprotection conditions known in the art.
  • the product is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.
  • the compound of Formula 401 in a polar solvent such as a mixture of tetrahydrofuran and water, is reacted with a compound of Formula 402 in the presence of a catalyst, such as [(di(l-adamantyl)-butylphosphine)-2-(2'-arnino-l,l'-biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3), and a base, such as tripotassium phosphate, to give a compound of Formula 403.
  • a catalyst such as [(di(l-adamantyl)-butylphosphine)-2-(2'-arnino-l,l'-biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3)
  • a base such as tripotassium phosphate
  • the compound of Formula 501 in a polar solvent such as dichloromethane
  • a protecting agent such as dihydropyran
  • an acid catalyst such as pyridinium p-toluenesulfonate
  • a compound of Formula 502 in a polar solvent, such as tetrahydrofuran is reacted with a metalating agent, such as lithium chloro-(2,2,6,6-tetramethyl-l-piperidyl)magnesium chloride, and a brominating agent such as l,2-dibromo-l,l,2,2-tetrachloro-ethane to give a compound of Formula 503.
  • a metalating agent such as lithium chloro-(2,2,6,6-tetramethyl-l-piperidyl)magnesium chloride
  • a brominating agent such as l,2-dibromo-l,l,2,2-tetrachloro-ethane
  • the compound of Formula 503 in a polar solvent such as 1 ,2-dimethoxyethane is reacted with a compound of Formula 504 in the presence of a catalyst, such as a combination of [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride, 4,4'- /?/.$( ! .
  • a catalyst such as a combination of [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride, 4,4'- /?/.$( ! .
  • the compound of Formula 505 in a polar solvent such as dichloroethane is reacted with a compound of Formula 506 in the presence of a catalyst, such as Cu(OAc)2,[2,2]bipyridinyl, and a base, such as sodium carbonate, to give a compound of Formula 507.
  • a catalyst such as Cu(OAc)2,[2,2]bipyridinyl
  • a base such as sodium carbonate
  • a metalating agent such as lithium chloro-(2,2,6,6-tetramethyl-l-piperidyl)magnesium chloride
  • a brominating agent such as l,2-dibromo-l,l,2,2-tetrachloro-ethane
  • a catalyst such as l,l’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
  • a base such as potassium carbonate
  • a catalyst such as 1,1’- bis(diphenylphosphino)ferrocene]palladium(II) dichloride
  • a base such as tripotassium phosphate
  • the compound of Formula 606 in a polar solvent is reacted with a compound of Formula 607 in the presence of a catalyst, such as [(di(l-adamantyl)-butylphosphine)-2-(2'- amino- l , r-biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3), and a base, such as tripotassium phosphate, to give a compound of Formula 608.
  • a catalyst such as [(di(l-adamantyl)-butylphosphine)-2-(2'- amino- l , r-biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3)
  • a base such as tripotassium phosphate
  • a compound of Formula 701 in a polar solvent such as N,N-dimethylformamide
  • an iodinating agent such as N-iodosuccinimide
  • the compound of Formula 702 in a polar solvent, such as N,N- dimethylformamide is reacted with a protecting agent, such as 2- (trimethylsilyl)ethoxymethyl chloride, in the presence of a base, such as sodium hydride, to give a compound of Formula 703.
  • a catalyst such as [(di(l -adamantyl)-butylphosphine)-2-(2'-amino-l ,1'- biphenyl)]palladium(II) methanesulfonate (cataCXium Pd G3)
  • a base such as tripotassium phosphate
  • a metalating agent such as lithium chloro-(2,2,6,6-tetramethyl-l-piperidyl)magnesium chloride
  • a brominating agent such as 1 ,2-dibromo- 1 , 1 ,2,2-tetrachloro-ethane
  • the compound of Formula 706 in a polar solvent such as tetrahydrofuran
  • a catalyst such as 1,1’- bis(diphenylphosphino)ferrocene Ipalladium(ll) dichloride
  • a base such as tripotassium phosphate
  • the compound of Formula 708 in a polar solvent, such as dichloromethane is reacted with a deprotecting agent, such as trifluoroacetic acid, to give a compound of Formula 709.
  • the compound of Formula 709 in a polar solvent, such as dichloromethane is reacted with a compound of Formula 710 in the presence of a base, such as potassium hydroxide, to give a compound of Formula 711.
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um;mobile phase: [water (FA) -ACN];gradient:20%-50% B over 10 min).
  • LCMS showed a peak (65%) with the mass of tert-butyl 6- (l-cyclopropyl-7-fluoro-4-isopropyl-6-tributylstannyl-pyrazolo[4,3-c]pyridin-3-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate and product.
  • the reaction was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic layer was washed with brine (20 mL x 3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure.
  • Step 3 6-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3- c]pyridin-6-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine
  • LCMS showed tert-butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro- benzothiophen-4-yl]-4-(2-cyanoethyl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-3-yl]- 3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (47%) with desired mass.
  • the mixture was diluted with dichloromethane (20 mL), neutralized with saturated NaHCCL aqueous solution (20 mL), the organic phase was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure.
  • LCMS showed tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro- 4-isobutyl-pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (50%) with desired mass.
  • the mixture was diluted with water (10 mL), the mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were concentrated under reduced pressure.
  • Step 3 3-[6-[6-amino-2-methyl-3-(trifluoroinethyl)-4-pyridyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)- l-cycIopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4-yl]propenamide
  • Example 52 3-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-3-(3- azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-pyrazolo[4,3-c]pyridin-4- yl]propanamide (13.9 mg, 22.51 pmol, 24.41% yield, 100% purity, TFA) as a white solid.
  • Step 6 2-[3-(3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexan-6-yl)-6-chloro-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-l-yl]cyclopropanecarboxylic acid
  • Step 8 tert-butyl 6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-7-fluoro-4-isopropyl-l-[2- (methyIcarbamoyl)cyclopropyl]pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane- 3-carboxylate
  • Step 2 2-[6-[6-amino-2-methyl-3-(trifluoromethyI)-4-pyridyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)- 7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-l-yl]cyclopropanecarbonitriIe [0247] Prepared from tert-butyl 6-[6-chloro-l-(2-cyanocyclopropyl)-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate via Suzuki coupling/TFA deprotection as described for Example 67.
  • Step 8 tert-butyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropyI-7-fluoro-4-isopropyl-pyrazoIo[4,3-c]pyridin-3-yl]-2-(methyIcarbamoyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate
  • Step 9 (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-N-methyI-3-azabicyclo[3.1.0]hexane-2- carboxamide
  • LCMS showed tert-butyl (lR,2S,5S,6R)-6-[6-[6- amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl]-2-(methylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass.
  • Step 2 cyclopropyl (lR,2S,5S,6R)-6-[6-[6-ainino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-2-carboxylate
  • LCMS showed 11% of tert-butyl (lR,2S,5S,6R)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-(6-chloro-l-cyclopropyl-7-fluoro-4-isopropyl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate remained and a peak (64%) with desired mass.
  • the mixture was diluted with water (10 mL), the mixture was extracted with ethyl acetate (10 mL x 3), and the organic layers were concentrated under reduced pressure.
  • LCMS showed tert-butyl (lR,2S,5S,6R)-6-[6-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak with desired mass. The mixture was concentrated under reduced pressure.
  • tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]- 2-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was prepared similarly to Example 59 via Suzuki coupling of tert-butyl (3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4-(trifluoromethoxy)phenyl)carbamate.
  • LCMS showed mass of tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-formyl-3- azabicyclo[3.1.0]hexane-3-carboxylate and desired mass in the same peak, the mixture was stirred at 0 °C for another 1 hour, LCMS showed mass of tert-butyl (lR,2S,5S,6R)-6-[6-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrazolo[4,3-c]pyridin
  • Step 3 l-[(lR,2S,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yl]ethanol
  • Step 2 l-[(lR,2S,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yI]-3-azabicydo[3.1.0]hexan-2-yI]ethanone
  • Step 3 2-[(lR,2R,5S,6R)-6-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7- fluoro-4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexan-2-yI]ethanol
  • LCMS showed tert-butyl (lR,2R,5S,6R)-6-[6- [5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro- 4-isopropyl-pyrazolo[4,3-c]pyridin-3-yl]-2-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate was consumed and main peak with desired mass.
  • Step 1 tert-butyl (lR,2S,5S,6R)-6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cydopropyI-7-fluoro-4-isopropyl-pyrazoIo[4,3-c]pyridin-3- yl]-2-(2-hydroxyethylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • LCMS showed tert-butyl 6-(4-bromo-6-chloro-l-cyclopropyl-7-fluoro-pyrazolo[4,3- c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed completely and a peak (29%) with desired mass.
  • the mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with brine (10 mL x 3), the organic layers were combined together, dried over Na2SC>4, filtered and the filtrate was concentrated under reduced pressure.
  • Step 2 4-[3-(3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-4-isobutyl-pyrazolo[4,3- c]pyridin-6-yl]-6-methyl-5-(trifluoromethyl)pyridin-2-amine [0337] Prepared from tert-butyl 6-(6-chloro-l-cyclopropyl-7-fluoro-4-isobutyl- pyrazolo[4,3-c]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate similarly to Example 65.
  • Step 3 tert-butyl 6-[6-[5-amino-3-fhioro-2-(trifluoromethoxy)phenyl]-l-cydopropyl-7-fluoro-4- isopropyI-2-(tetrahydropyran-2-yloxymethyl)pyrrolo[3,2-c]pyridin-3-yI]-3- azabicyclo[3.1.0]hexane-3-carboxylate
  • Step 2 tert-butyl-[(6-chloro-l-cyclopropyl-7-fhioro-3-iodo-pyrrolo[3,2-c]pyridin-2- yl)methoxy] -dimethyl-silane
  • the suspension was degassed under vacuum and purged with H2 (50Psi) several times.
  • the mixture was stirred under H2 (50 psi) at 25 °C for 32 hours.
  • LCMS showed the starting material was consumed completely and a peak (62%) with desired mass.
  • the mixture was filtered through celite and the filtrate was concentrated in vacuum.
  • Step 8 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2- (chloromethyl)-l-cyclopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate
  • Step 2 N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicycIo[3.1.0]hexan-6-yl)- l-cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]-2-cyano- acetamide
  • LCMS showed tert-butyl (lR,5S)-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l,4-dicyclopropyl-7-fluoro-2- (3-hydroxyprop-l-ynyl)pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass.
  • reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 19%-49% B over 10.0 min), the eluent was freeze dried over to afford 3-[6- [5- amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l,4- dicyclopropyl-7-fluoro-pyrrolo[3,2-c]pyridin-2-yl]prop-2-yn-l-ol (11.8 mg, 18.38 pmol, 13.69% yield, 92% purity, FA) as a white solid.
  • Step 1 tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cycIopropyl-2-(4,5-dihydro-lH-imidazol-2-yl)-7-fluoro-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • Ethane- 1 ,2-diamine (83.39 mg, 1.39 mmol, 92.86 pL, 10 eq) was added to a mixture of tert-butyl 6-[6-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2-formyl-4-isopropyl-pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 138.75 pmol, 1 eq) and 4A MS (50 mg) in t-BuOH (1 mL).
  • reaction mixture was concentrated under reduced pressure to give a residue which was purified by reversed-phase HPLC(column: Phenomenex Luna Cl 8 150*25mm*10um; mobile phase: [HzO(0. 1% TFA)- ACN]; gradient:5%-35% B over 15.0 min) to afford crude product.
  • the crude product was purified by reversed-phase HPLC(column: Waters Xbridge C18 150*25mm*5um;mobile phase: [FLOQOmM NFLHCC ⁇ -ACN]; gradient: 35%-65% B over 10.0 min) to afford 3-[3- (3-azabicyclo[3.1.0]hexan-6-yl)-l-cyclopropyl-7-fluoro-2-(lH-imidazol-2-yl)-4-isopropyl- pyrrolo[3,2-c]pyridin-6-yl]-5-fluoro-4-(trifluoromethoxy)aniline (1.3 mg, 2.26 pmol, 8.57% yield, 97% purity) as a white solid.
  • Step 2 N-[[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicydo[3.1.0]hexan-6-yl)- l-cycIopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]methyl]acetamide [0412] To a solution of tert-butyl 6-[2-(acetamidomethyl)-6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-4- isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (27 mg, 35.35 pmol, 1 eq) in DCM (0.6 mL) was added TFA (1.21 mg
  • LCMS showed tert-butyl (lS,5R)-6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-2-(chloromethyl)-l- cyclopropyl-7-fhioro-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate was consumed and main peak with desired mass.
  • Step 1 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-4-isopropyl-2-[[(3-methyloxetan-3-yl)amino]methyl]pyrrolo[3,2- c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • Step 2 2-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]acetonitrile
  • Step 1 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cydopropyI-7-fluoro-4-isopropyl-2-(oxiran-2-yl)pyrrolo[3,2-c]pyridin-3-yl]-3- azabicyclo[3.1.0]hexane-3-carboxylate
  • Step 7 l-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cydopropyl-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]-2-methyl-propan-2-ol
  • Step 4 [5-fhioro-6-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-l-naphthyl]-4- methyl-l-[(3R)-3-methyl-3-tetrahydropyran-2-yloxy-l-piperidyI]-2,7-naphthyridin-3- yl]methyl methanesulfonate
  • Step 1 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyl-7-fluoro-2-[hydroxy-[l-(2-trimethylsilylethoxymethyl)imidazol-2- yl]methyl]-4-isopropyI-pyrroIo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3- carboxylate
  • LCMS showed tert-butyl 6-[6-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l-cyclopropyl-7-fluoro-2- formyl-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate was consumed and main peak with desired mass.
  • Step 1 tert-butyl 6-[6-[5-(tert-butoxycarbonyIamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-l- cyclopropyI-7-fluoro-2-(l-hydroxyethyl)-4-isopropyl-pyrrolo[3,2-c]pyridin-3-yI]-3- azabicyclo[3.1.0]hexane-3-carboxylate
  • Step 2 l-[6-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-3-(3-azabicyclo[3.1.0]hexan-6-yl)-l- cyclopropyI-7-fluoro-4-isopropyl-pyrrolo[3,2-c]pyridin-2-yl]ethanol

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés, et des sels de ceux-ci, qui inhibent des mutants NRAS ciblés, des formulations pharmaceutiques et des méthodes de traitement de maladies médiées par NRAS, telles que certains cancers.
PCT/US2025/024118 2024-04-11 2025-04-10 Composés hétérocycliques utilisés en tant qu'inhibiteurs de nras Pending WO2025217430A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011050245A1 (fr) * 2009-10-23 2011-04-28 Yangbo Feng Hétéroaryles bicycliques formant inhibiteurs de la kinase
US20170050957A1 (en) * 2013-03-15 2017-02-23 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US11242334B2 (en) * 2017-08-22 2022-02-08 Js Innopharm (Shanghai) Ltd. Heterocyclic compounds as kinase inhibitors, compositions comprising the heterocyclic compound, and methods of use thereof
US20220251098A1 (en) * 2017-06-05 2022-08-11 Ptc Therapeutics, Inc. Compounds for treating huntington's disease

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011050245A1 (fr) * 2009-10-23 2011-04-28 Yangbo Feng Hétéroaryles bicycliques formant inhibiteurs de la kinase
US20170050957A1 (en) * 2013-03-15 2017-02-23 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US20220251098A1 (en) * 2017-06-05 2022-08-11 Ptc Therapeutics, Inc. Compounds for treating huntington's disease
US11242334B2 (en) * 2017-08-22 2022-02-08 Js Innopharm (Shanghai) Ltd. Heterocyclic compounds as kinase inhibitors, compositions comprising the heterocyclic compound, and methods of use thereof

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